MD Research News – Issue 423 – 24 May 2019

Drug treatment

Br J Ophthalmol. 2019 May 11. pii: bjophthalmol-2019-313907.

Safety and tolerability of ranibizumab in uni/bilateral neovascular age-related macular degeneration: 12-month TWEYEs study.

Bandello F, Staurenghi G, Ricci F, Midena E, Viola F, Lupieri Sinibaldi T, Colombo L, Peruzzi E, Bassanini S.

Background: To evaluate the safety and tolerability of ranibizumab 0.5 mg in patients with uni/bilateral neovascular age-related macular degeneration (nAMD) and best-corrected visual acuity (BCVA)<2/10 and/or second eye affected, regardless of BCVA.

Methods: In this 12-month, prospective, multicentre, open-label, single arm, pragmatic interventional study, patients (N=941) aged ≥ 50 years were to receive ranibizumab as per approved label, monthly until maximum stable visual acuity (VA) was achieved (initially, three or more injections may be required). Thereafter, patients were to be monitored monthly for VA and treatment was to be resumed if VA was reduced due to disease activity.

Results: Of the 936 patients treated with ranibizumab at least once during the study, 823/113 were unilaterally/bilaterally (not simultaneously) treated . The mean (SD) number of ranibizumab injections during the study was 5.4 (2.9)/10.6 (5.0) injections in uni/bilaterally treated patients. Three systemic drug-related adverse events (AEs) (all serious, all in unilaterally treated patients) and 18 systemic AE of special interest (AESIs) (11 serious, 16/2 in unilaterally/bilaterally treated patients) occurred during the study. The annual incidence rate (AIR) (events/1000 person-years) for systemic drug-related AEs, considering a 15-day/30-day risk period, 11.0/8.5 for unilaterally treated patients. Considering the same risk period, the AIR (events/1000 person-years) for systemic AESIs for unilaterally treated patients was 22.1/19.9. Considering a 30-day risk period, the AIR (events/1000 treated eye-years) of ocular drug-related AEs was 23 and AESIs was 11.5.

Conclusions: The low incidence of AEs and AESIs demonstrated the good safety and tolerability of ranibizumab in unilaterally/bilaterally treated patients with nAMD in this real-world setting.

PMID: 31079057 DOI: 10.1136/bjophthalmol-2019-313907

Eur J Ophthalmol. 2019 May 14:1120672119848961.

Intravitreal aflibercept efficacy in neovascular age-related macular degeneration with suboptimal response to anti-vascular endothelial growth factor-A therapy.

Monés J, Biarnés M; Macbeth Study Group.

Importance: To provide new insights into aflibercept effect in non-naive-treated patients with neovascular age-related macular degeneration.

Purpose: To assess the efficacy of intravitreal aflibercept in patients with neovascular age-related macular degeneration without optimal response to previous anti-vascular endothelial growth factor A therapy.

Design: Single-arm, multi-centre, prospective study.

Participants: Patients ⩾50 years with active neovascular age-related macular degeneration, best-corrected visual acuity between 20/32 and 20/320 with suboptimal response to ranibizumab or bevacizumab.

Methods: Aflibercept was administered monthly (3-first months), and bimonthly thereafter until month 8. Anatomical and functional outcomes were assessed.

Main Outcome Measure: Percentage of eyes without intra or subretinal fluid on optical coherence tomography after 3-monthly loading doses of aflibercept.

Results: A total of 46 patients were included. At week 12, 45.7% (95% confidence interval: 31.5%-60.1%) of eyes showed no fluid on optical coherence tomography. The mean (standard deviation) best-corrected visual acuity increased from 65.1 (8.3) to 69.6 (8.1) letters (+4.5 (5.8) p < 0.0001) and was stabilized at week 40 as compared to baseline. Mean central macular thickness decreased from 430 (119) µm to 323 (100) µm at week 12 (-107 (90) µm, p < 0.0001) and was reduced at week 40 (-46 (111) µm, p = 0.0056). At week 40, 21.7% (95% confidence interval: 9.8%-33.7%) had no fluid. There was a case of presumed noninfectious endophthalmitis that was successfully managed.

Conclusion: Almost half of patients presented no fluid on optical coherence tomography at week 12, and there was a clinically significant improvement in best-corrected visual acuity. At week 40, one in five patients did not show intra or subretinal fluid, central macular thickness decreased and best-corrected visual acuity was stabilized compared to baseline.

PMID: 31088111 DOI: 10.1177/1120672119848961

 

Medicine (Baltimore). 2019 May;98(20):e15735.

Intravitreal ranibizumab injection at the end of vitrectomy for diabetic vitreous hemorrhage (Observational Study).

Liang X, Zhang Y, Wang JX, Wang LF, Huang WR, Tang X.

Abstract: To evaluate the outcomes and complications of intravitreal injections of ranibizumab in patients during pars plana vitrectomy for treatment of diabetic vitreous hemorrhage. This retrospective, observational, comparative study included 103 patients (103 eyes) who underwent pars plana vitrectomy for treatment of diabetic vitreous hemorrhage. Sixty-six patients received an intravitreal injection of 0.05 mg (0.05 cc) of ranibizumab at the end of surgery. Main outcome measures were the occurrence of recurrent early vitreous hemorrhage, reoperation, intraocular pressure, best corrected visual acuity. Mean follow-up time was 6 months. The rate of rebleeding in the intravitreal ranibizumab (IVR) group was 6.1% (4 eyes), which is significantly lower than the control group (24.3%, 9 eyes, P < .01). The incidence of postoperative diabetic vitreous hemorrhage (PDVH) was significantly lower in the IVR group than the control group, OR=0.26, 95% CI= (0.06, 0.95). Visual acuity 6 months after operation was better in IVR group (P<.01) There was no difference in mean intraocular pressure between the 2 groups (P=.56). The present clinical study suggests that intravitreal injection of ranibizumab is effective in the prevention of postoperative diabetic vitreous hemorrhage in eyes undergoing pars plana vitrectomy for the treatment of diabetic vitreous hemorrhage.

PMID: 31096535 DOI: 10.1097/MD.0000000000015735

 

Imaging

J Ophthalmol. 2019 Apr 9;2019:6319581.

Automated detection of macular diseases by optical coherence tomography and artificial intelligence machine learning of optical coherence tomography images.

Kuwayama S, Ayatsuka Y, Yanagisono D, Uta T, Usui H, Kato A, Takase N, Ogura Y, Yasukawa T.

Purpose: Although optical coherence tomography (OCT) is essential for ophthalmologists, reading of findings requires expertise. The purpose of this study is to test deep learning with image augmentation for automated detection of chorioretinal diseases.

Methods: A retina specialist diagnosed 1,200 OCT images. The diagnoses involved normal eyes (n=570) and those with wet age-related macular degeneration (AMD) (n=136), diabetic retinopathy (DR) (n=104), epiretinal membranes (ERMs) (n=90), and another 19 diseases. Among them, 1,100 images were used for deep learning training, augmented to 59,400 by horizontal flipping, rotation, and translation. The remaining 100 images were used to evaluate the trained convolutional neural network (CNN) model.

Results: Automated disease detection showed that the first candidate disease corresponded to the doctor's decision in 83 (83%) images and the second candidate disease in seven (7%) images. The precision and recall of the CNN model were 0.85 and 0.97 for normal eyes, 1.00 and 0.77 for wet AMD, 0.78 and 1.00 for DR, and 0.75 and 0.75 for ERMs, respectively. Some of rare diseases such as Vogt-Koyanagi-Harada disease were correctly detected by image augmentation in the CNN training.

Conclusion: Automated detection of macular diseases from OCT images might be feasible using the CNN model. Image augmentation might be effective to compensate for a small image number for training.

PMID: 31093370 PMCID: PMC6481014 DOI: 10.1155/2019/6319581

 

Am J Ophthalmol. 2019 May 9. pii: S0002-9394(19)30219-3.

Quantitative assessment of choriocapillaris flow deficits in eyes with advanced age-related macular degeneration versus healthy eyes.

Alagorie AR, Verma A, Nassisi M, Sadda SR.

Purpose: To compare choriocapillaris (CC) flow deficits in eyes with geographic atrophy (GA) or choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) and age-matched healthy control subjects.

Design: Cross-sectional study.

Methods: Patients with GA due to AMD, CNV due to AMD, and age-matched healthy subjects presenting to the Doheny-UCLA Eye Centers were enrolled in this cross-sectional IRB-approved study. Swept-source optical coherence tomography angiography (SS-OCTA) was performed using a Zeiss PLEX Elite instrument with a 6 × 6 mm scan pattern centered on the fovea. Two repeated volume scans were acquired to allow for image averaging. The instrument pre-defined en face slab of the CC was used to isolate and display the CC. Both the structural and OCTA slabs from this location were exported for averaging and signal compensation using Image J. The resultant image was then binarized. The CC flow deficit percentage (FD %) was computed in four peripheral 1 mm × 1 mm squares located at the corners of the images to allow comparison between equidistant regions unaffected by atrophy or CNV.

Results: Twenty eyes of twenty subjects were enrolled in each of the three groups (CNV, GA, normal) for this study. The average CC FD % of the 4 peripheral squares was 17.24% ± 2.86% in GA eyes, 15.55% ± 1.03% in CNV eyes, and 15.31% ± 0.93% in healthy controls of a similar age. The FD% in GA eyes was significantly greater than in both normal eyes and eyes with CNV (p= 0.012 and 0.038 respectively). The difference in FD% was not significantly different between CNV eyes and normal eyes for the tested peripheral macular regions (p= 0.678).

Conclusions: The choriocapillaris in peripheral macular regions in eyes with GA shows greater impairment than in eyes with CNV.

PMID: 31078531 DOI: 10.1016/j.ajo.2019.04.037

 

JAMA Ophthalmol. 2019 May 16.

Evaluation of a remote diagnosis imaging model vs dilated eye examination in referable macular degeneration.

Hadziahmetovic M, Nicholas P, Jindal S, Mettu PS, Cousins SW.

Importance: In improving clinical outcomes, developing a sustainable, transformative care delivery model is important for accessible, efficient, low-cost, high-quality community-based imaging and diagnosis of retinal diseases.

Objective: To test the feasibility and accuracy of the remote diagnosis imaging model as a clinical screening tool to facilitate the identification of referable macular degeneration.

Design, Setting, and Participants: A nonrandomized study of 159 patients was conducted in sites with a relatively high disease prevalence (Duke University Health System endocrinology clinic and 2 Duke University Health System assisted living centers in North Carolina). All patients underwent remote diagnosis imaging, defined as color fundus photography (CFP) and optical coherence tomography (OCT) of nondilated pupils, acquired by nonexpert imagers using a retinal imaging device located at the point of service. The criterion standard examination was defined as a traditional dilated eye examination performed by retinal specialists. Deidentified remote diagnosis images were graded for interpretability and presence of referable macular degeneration, defined as any condition requiring a retinal specialist attention. Data analysis was performed from November 20, 2015, to February 10, 2019.

Main Outcomes and Measures: Primary outcome was feasibility of the remote retinal imaging. Secondary outcomes were operational characteristics and diagnostic and referral accuracy.

Results: Of the 159 patients included in the study, the mean (SD) age of enrolled participants was 65 (17) years, with a female to male ratio of 1.3 to 1. Most patients were white (111 [69.8%]), 44 were black patients (27.7%), approximately 1% were Asian patients and Hispanic patients, and 2 patients declined to disclose their race/ethnicity. Thirty-five eyes (22.0%) were determined to require referral to the retinal specialist by criterion standard examination. Remote diagnosis image interpretability was better when OCT was used compared with CFP (241 [96.4%] vs 164 [65.6%]). Remote diagnosis had high diagnostic accuracy in identifying referable macular degeneration: OCT and CFP both had 94% sensitivity (95% CI, 84%-98%), and OCT had specificity higher than for CFP (93% [95% CI, 87%-96% ] vs 63% [95% CI, 53%-71%]). Substantial agreement was found between the criterion standard and OCT (κ = 0.83; 95% CI, 0.76-0.91; P < .001) and between the criterion standard and CFP (κ = 0.76; 95% CI, 0.64-0.87; P < .001). The nonvalidated patient satisfaction survey revealed that 122 participants (76.7%; mean score, 4.16; 95% CI, 3.98-4.35) preferred remote imaging over the standard care examination.

Conclusions and Relevance: Remote diagnosis imaging and a standard examination by a retinal specialist appeared equivalent in identifying referable macular degeneration in patients with high disease prevalence; these results may assist in delivering timely treatment and seem to warrant future research into additional metrics.

PMID: 31095245 DOI: 10.1001/jamaophthalmol.2019.1203

 

Epidemiology

Ophthalmic Surg Lasers Imaging Retina. 2019 May 1;50(5):e140-e157.

Classification of strokes in patients receiving intravitreal anti-vascular endothelial growth factor.

Starr MR, Dalvin LA, AbouChehade JE, Damento GM, Garcia MD, Shah SM, Hodge DO, Meissner I, Iezzi R, Bakri SJ.

Background and Objective: The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations.

Patients and Methods: We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified.

Results: A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all).

Conclusion: The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations.

PMID: 31100168 DOI: 10.3928/23258160-20190503-14

 

Pathogenesis

Int J Mol Sci. 2019 May 14;20(10). pii: E2374.

Role of mitochondrial DNA damage in ROS-mediated pathogenesis of age-related macular degeneration (AMD).

Kaarniranta K, Pawlowska E, Szczepanska J, Jablkowska A, Blasiak J.

Abstract: Age-related macular degeneration (AMD) is a complex eye disease that affects millions of people worldwide and is the main reason for legal blindness and vision loss in the elderly in developed countries. Although the cause of AMD pathogenesis is not known, oxidative stress-related damage to retinal pigment epithelium (RPE) is considered an early event in AMD induction. However, the precise cause of such damage and of the induction of oxidative stress, including related oxidative effects occurring in RPE and the onset and progression of AMD, are not well understood. Many results point to mitochondria as a source of elevated levels of reactive oxygen species (ROS) in AMD. This ROS increase can be associated with aging and effects induced by other AMD risk factors and is correlated with damage to mitochondrial DNA. Therefore, mitochondrial DNA (mtDNA) damage can be an essential element of AMD pathogenesis. This is supported by many studies that show a greater susceptibility of mtDNA than nuclear DNA to DNA-damaging agents in AMD. Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy. However, we know far less about mtDNA than its nuclear counterparts. Further research should measure DNA damage in order to compare it in mitochondria and the nucleus, as current methods have serious disadvantages.

PMID: 31091656 DOI: 10.3390/ijms20102374

 

Sci Rep. 2019 May 16;9(1):7475.

A lasered mouse model of retinal degeneration displays progressive outer retinal pathology providing insights into early geographic atrophy.

Ibbett P, Goverdhan SV, Pipi E, Chouhan JK, Keeling E, Angus EM, Scott JA, Gatherer M, Page A, Teeling JL, Lotery AJ, Arjuna Ratnayaka J.

Abstract: Early stages of geographic atrophy (GA) age-related macular degeneration is characterised by the demise of photoreceptors, which precedes the loss of underlying retinal pigment epithelial (RPE) cells. Sight-loss due to GA has no effective treatment; reflecting both the complexity of the disease and the lack of suitable animal models for testing potential therapies. We report the development and characterisation of a laser-induced mouse model with early GA-like pathology. Retinas were lasered at adjacent sites using a 810 nm laser (1.9 J/spot), resulting in the development of confluent, hypopigmented central lesions with well-defined borders. Optical Coherence Tomography over 2-months showed progressive obliteration of photoreceptors with hyper-reflective outer plexiform and RPE/Bruch's membrane (BrM) layers within lesions, but an unaffected inner retina. Light/electron microscopy after 3-months revealed lesions without photoreceptors, leaving the outer plexiform layer apposed to the RPE. We observed outer segment debris, hypo/hyperpigmented RPE, abnormal apical-basal RPE surfaces and BrM thickening. Lesions had wedge-shaped margins, extended zones of damage, activated Müller cells, microglial recruitment and functional retinal deficits. mRNA studies showed complement and inflammasome activation, microglial/macrophage phagocytosis and oxidative stress providing mechanistic insights into GA. We propose this mouse model as an attractive tool for early GA studies and drug-discovery.

PMID: 31097765 DOI: 10.1038/s41598-019-43906-z